Rett Syndrome (RTT) is a developmental disorder linked to mutations in the X chromosome gene methyl CpG-binding protein 2 (MeCP2). MeCP2 codes for a protein that regulates transcription. It forms a transcription repressor complex that binds to methylated gene sequences, and induces chromatin condensation.
Patients with Rett Syndrome, who are almost exclusively females, show distinctive hand movements, slowed brain growth, regression of language and motor skills, seizures, cognitive impairment and mental retardation. Cortical structure is relatively preserved, but dendritic structure is altered and dendritic spines appear structurally immature.
Mouse models of Rett Syndrome have been made (Chen et al., Nat Genet. 27 (3):327-31, 2001; Guy et al., Nat Genet. 27 (3):322-6, 2001; Shahbazian et al., Neuron 35 (2):243-54, 2002). MeCP2 knockout (KO) mice show movement and respiratory phenotype, smaller pyramidal neurons, and electrophysiological abnormalities suggestive of synaptic and neuronal immaturity. A truncating mutation of MeCP2 leads to motor and social dysfunction, alterations in synaptic plasticity and memory.
Restoration of MeCP2 levels in a conditional MeCP2 KO mouse model restores movement function (Guy et al., Science 315 (5815):1143-7, 2007). Enhanced BDNF expression in KO mice reverses the movement and electrophysiological phenotype (Chang et al., Neuron 49 (3):341-8, 2006). These and other data suggest that synapses remain in an immature state in the mouse models, and appropriate treatments even late in development can re-establish function.